BACE1 is the rate-limiting enzyme for Abeta generation in Alzheimer's disease (AD) and is a prime drug target. BACE1 inhibitor drugs have recently entered into clinical trials. However, the safety and efficacy of these agents are unknown. BACE1 deficient (BACE1-/-) mice exhibit neurological phenotypes, suggesting BACE1 inhibitors may incur mechanism-based toxicities. However, BACE1-/- phenotypes may reflect consequences of BACE1 deficiency during development, in which case BACE1 inhibitors may be free of side effects. Even more uncertain is the stage of AD at which BACE1 inhibition would be most efficacious. This R01 will address three questions that are critical for the development of safe, effective BACE1 inhibitors for AD: 1) Is BACE1 required in the adult, or dispensable after development? 2) Does developmental compensation occur in BACE1-/- mice, preventing BACE1 null phenotypes that would otherwise appear in the adult? 3) At what stage of AD will BACE1 inhibitor drugs be most effective: before (prevention) or after (treatment) symptom onset? To address these questions, we have generated conditional BACE1 knockout (BACE1fl/fl) mice.
In Aim 1, we will determine whether BACE1 gene inactivation in the adult causes neurological phenotypes that are observed in BACE1-/- mice. BACE1fl/fl mice will be bred with CamKII?-iCre mice to inactivate BACE1 in excitatory neurons of the adult forebrain.
In Aim 2, we will determine whether BACE1 gene inactivation in the adult produces novel BACE1 null phenotypes in the nervous system and periphery. BACE1fl/fl mice will be bred with R26-cre-ERT2 mice to inactivate BACE1 globally following administration of tamoxifen.
In Aim 3, we will determine whether BACE1 gene inactivation in the adult will reduce amyloid burden after the start of plaque deposition. BACE1fl/fl;R26-cre-ERT2 mice will be bred with APPswe/PS1deltaE9 amyloid plaque model mice to inactivate BACE1 globally following administration of tamoxifen. For all Aims, mice will be aged and analyzed for behavior, electrophysiology, histology, and biochemistry. In addition, Aim 3 mice will be analyzed for amyloid plaque load and Abeta levels. Together, these Aims will determine the overall utility of BACE1 inhibition as an AD therapeutic strategy in terms of its potential side effect profile and efficacy.

Public Health Relevance

Alzheimer's disease (AD) is an intractable neurodegenerative disorder with no disease-modifying therapy. BACE1 inhibitors are currently in clinical trials for AD, but the safety and efficacy of these agents are unknown. This application will determine the overall utility of BACE1 inhibition as a therapeutic strategy in terms of its potential side effect profile and efficacy for AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG022560-12
Application #
8691629
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2003-09-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
$316,725
Indirect Cost
$111,725
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Liu, Peng; Reichl, John H; Rao, Eshaan R et al. (2017) Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-? Protein Precursor Transgenic Mice. J Alzheimers Dis 56:743-761
Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109
Sasaguri, Hiroki; Nilsson, Per; Hashimoto, Shoko et al. (2017) APP mouse models for Alzheimer's disease preclinical studies. EMBO J 36:2473-2487
Yan, Riqiang; Fan, Qingyuan; Zhou, John et al. (2016) Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer's disease. Neurosci Biobehav Rev 65:326-40
Sadleir, Katherine R; Eimer, William A; Cole, Sarah L et al. (2015) A? reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level. Mol Neurodegener 10:1
Vassar, Robert; Kuhn, Peer-Hendrik; Haass, Christian et al. (2014) Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem 130:4-28
Kandalepas, Patty C; Vassar, Robert (2014) The normal and pathologic roles of the Alzheimer's ?-secretase, BACE1. Curr Alzheimer Res 11:441-9
Yan, Riqiang; Vassar, Robert (2014) Targeting the ? secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol 13:319-29
Vassar, Robert (2014) BACE1 inhibitor drugs in clinical trials for Alzheimer's disease. Alzheimers Res Ther 6:89
Buggia-Prévot, Virginie; Fernandez, Celia G; Riordan, Sean et al. (2014) Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase. Mol Neurodegener 9:1

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